High frequency stimulation of the subthalamic nucleus evokes striatal dopamine release in a large animal model of human DBS neurosurgery

Abstract

Subthalamic nucleus deep brain stimulation (STN DBS) ameliorates motor symptoms of Parkinson’s disease, but the precise mechanism is still unknown. Here, using a large animal (pig) model of human STN DBS neurosurgery, we utilized fast-scan cyclic voltammetry in combination with a carbon-fiber microelectrode (CFM) implanted into the striatum to monitor dopamine release evoked by electrical stimulation at a human DBS electrode (Medtronic 3389) that was stereotactically implanted into the STN using MRI and electrophysiological guidance. STN electrical stimulation elicited a stimulus time-locked increase in striatal dopamine release that was both stimulus intensity- and frequency-dependent. Intensity-dependent (1–7 V) increases in evoked dopamine release exhibited a sigmoidal pattern attaining a plateau between 5 to 7 V of stimulation, while frequency-dependent dopamine release exhibited a linear increase from 60 to 120 Hz and attained a plateau thereafter (120–240 Hz). Unlike previous rodent models of STN DBS, optimal dopamine release in the striatum of the pig was obtained with stimulation frequencies that fell well within the therapeutically effective frequency range of human DBS (120–180 Hz). These results highlight the critical importance of utilizing a large animal model that more closely represents implanted DBS electrode configurations and human neuroanatomy to study neurotransmission evoked by STN DBS. Taken together, these results support a dopamine neuronal activation hypothesis suggesting that STN DBS evokes striatal dopamine release by stimulation of nigrostriatal dopaminergic neurons.

The Effects of Levodopa and Deep Brain Stimulation on Subthalamic Local Field Low-Frequency Oscillations in Parkinson's Disease

“…Although exactly how DBS modulates STN LF activity remains open to conjecture, electrical polarization around the DBS electrode could modulate activity in STN neurons and, given that we recorded similar STN LF power in patients on medication and on DBS, suggests that polarization could act similarly to levodopa. Some studies have highlighted the striatal dopamine release during high-frequency DBS [41,42,43,44]. Hence, again given the similar STN LF power changes recorded on medication and during DBS, the DBS-induced striatal dopamine release and levodopa medication could correspond to the LF power increase in a similar manner [18,24].…”

Neuropsychiatric Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson Disease in China: A Prospectively Controlled Study

“…The immediate positive effects on psychiatric symptoms, such as depression, anxiety and fatigue, might be mediated through direct involvement of STN in fear-processing networks and limbic circuits, as well as indirect dopaminergic effects of STN-DBS [20,26,27]. The occurrence of anxiety and acute worsening of depression were most likely due to misplacing of electrodes ventrally to the STN [28], while optimal electrode positions can lead to immediate anti-depressive and mood-elevating effects [29].…”

The Nucleus Accumbens as a Potential Target for Central Poststroke Pain

“…37 We have previously reported that high-frequency stimulation of the subthalamic nucleus increases glutamate and dopamine levels in rats and large animal models. 38,39 Thus, it is not unreasonable to presume that high-frequency stimulation of the NAC may also result in glutamate and dopamine release, which could result in analgesia through unknown downstream effects.…”